Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents

ABSTRACT

There are disclosed compounds of the formula ##STR1## wherein R 1  is hydrogen or lower alkyl; 
     R 2  is C 3-7  alkyl or C 3-7  cycloalkyl; 
     R 3  is hydrogen, lower alkyl, carboxyloweralkyl, lower alkoxycarbonyl, lower alkoxycarbonyl loweralkyl, aryl or aralkyl; 
     R 4  is hydrogen, C 1-8  alkyl, ##STR2## B is a bond, NH or O; Y is O or S; 
     A is a bond or --C═C--; 
     n is 0-5; 
     R 5  is hydrogen when B is NH, or 
     R 5  is lower alkyl, C 3-8  cycloalkyl; aryl, substituted aryl, aralkyl, substituted aralkyl, aralkenyl, aralkenylalkyl or ##STR3## R 6  is hydrogen or halo; the dotted line represents an optional double bond; and 
     the pharmacologically acceptable salts thereof, which by virtue of their ability to selectively inhibit PDE IV, are bronchodilatory and anti-inflammatory and so are useful in the treatment of acute and chronic bronchial asthma and associated pathologies.

This invention relates to novel phenyl pyrazolidinones havingbronchodilator and antiinflammatory activity and being useful in thetreatment of asthma.

Asthma is a disease in which respiratory distress is produced as aresult of airway narrowing. This narrowing is caused largely by 1) theacute constriction of the respiratory smooth muscle that surrounds theairways and 2) chronic inflammation within the lung. Reversal ofbronchospasm and prevention of pulmonary inflammation, then, arecritical approaches to the relief of the symptoms of asthma.

One approach for reversing bronchospasm and also inhibiting inflammationis to elevate intracellular adenosine cyclic 3':5'-monophosphate (cAMP)in respiratory smooth muscle and inflammatory cells, respectively. Thecompound adenosine cyclic 3':5'-monophosphate is defined as a "secondmessenger" because it mediates a variety of effects performed byhormones, which are "first messengers". One of the more important rolesis in mediating bronchodilation [see Sutherland et al., Circulation, 37,279 (1968)]. The enzymatic mechanism for the inactivation of cyclic AMPhas been known for some time [see Butcher et al., Pharmacologist, 1, 63(1959)] and the enzyme responsible for this inactivation was identifiedas a magnesium dependent phosphodiesterase. The latter is capable ofhydrolyzing cyclic AMP to adenosine monophosphate. Subsequent researchhas established that the xanthine-based bronchodilators, such astheophylline and aminophylline, mediate their bronchodilating activityvia inhibition of cyclic AMP phosphodiesterase (PDE) [see Lancet 1970,1119]. Agents that elevate smooth muscle cAMP concentrations inducerapid bronchodilation and inhibit the release of inflammatory mediatorsfrom activated leukocytes [see Hardman, in Smooth Muscle, An Assessmentof Current Knowledge, Univ. of Texas Press, (1981); and Nielson et al.,American Review of Respiratory Disease, 137, 25 (1988)]. By virtue oftheir dual mechanisms of action, such compounds can function as highlyeffective anti-asthmatic drugs.

Cyclic AMP concentrations within the living cell are determined by boththe rate of its synthesis by adenylate cyclase and the rate of itsdegradation by phosphodiesterases. Thus, either stimulating adenylatecyclase or inhibiting PDEs in pulmonary tissues can result inanti-asthmatic activities. The most effective anti-asthmatic drugs arethose which demonstrate the ability to inhibit a specific PDE, oftencalled PDE IV, that selectively metabolizes cAMP and that is insensitiveto the modulatory effects of guanosine cyclic 3':5'-monophosphate (cGMP)and calcium. This PDE is found in both respiratory smooth muscle andinflammatory cells, and has been demonstrated to be a principleregulator of cAMP in these tissues [see Torphy and Cieslinski, MolecularPharmacology, 37, 206 (1990), and Dent et al., British Journal ofPharmacology, 90, 163P (1990)]. Moreover, a variety of phosphodiesteraseisozymes have been isolated from bronchial smooth muscles [see Silver etal., Eur. J. Pharmacol., 150, 85 (1988)] and their kinetics have beenstudied using a variety of inhibitors.

The compounds of this invention not only are selective inhibitors of PDEIV of pulmonary tissue, but also inhibit the influx of leukocytes intothe bronchial tissue. This influx is the cause of the inflammation whichcharacterizes chronic asthma, and can lead to pulmonary edema [seeNseuli et al., Ann. Allergy, 60, 379 (2988)]. Since the compounds of theinvention inhibit leukocyte influx into the bronchoalveolar lavage, theycan also be used to prevent the onset of the inflammation which ischaracteristic of chronic asthmatic conditions. Consequently, thecompounds named in this invention are both bronchodilatory andantiinflammatory, and are effective in animal models of allergic andnonallergic asthma. However, because the compounds of the inventionpreferentially inhibit the PDE IV isozyme, they are more selective andsafer anti-asthmatics than nonselective PDE inhibitors currently usedfor the treatment of asthma, such as theophylline.

The invention provides novel compounds of the formula ##STR4## whereinR¹ is hydrogen or lower alkyl;

R² is C₃₋₇ alkyl or C₃₋₇ cycloalkyl;

R³ is hydrogen, lower alkyl, carboxyloweralkyl, lower alkoxycarbonyl,lower alkoxycarbonyl loweralkyl, aryl or aralkyl;

R⁴ is hydrogen, C₁₋₈ alkyl, ##STR5## B is a bond, NH or O; Y is O or S;

A is a bond or --C═C--;

n is 0-5;

R⁵ is hydrogen when B is NH, or

R⁵ is lower alkyl, C₃₋₈ cycloalkyl, aryl, substituted aryl, aralkyl,substituted aralkyl, aralkenyl, aralkenylalkyl or ##STR6## R⁶ ishydrogen or halo; the dotted line represents an optional double bond;and

the pharmacologically acceptable salts thereof.

The terms "lower alkyl" and "lower alkoxy" refer to moieties having 1 to6 carbon atoms in the carbon chain. The term "aryl" refers to aromaticmoieties having 6-10 carbon atoms, while "aralkyl" refers to moietieshaving 12-16 carbon atoms in the aromatic nucleus and associated alkylchain. The term "aralkenyl" refers to moieties having 12-16 carbon atomsin the aromatic nucleus and associated alkylene chain, while"aralkenylalkyl" refers to "aralkenyl" moieties whose alkenyl chain isfurther attached to a lower alkyl chain. The term "halo" refers tofluoro, chloro and bromo.

The especially preferred compounds are those having the formula ##STR7##wherein R¹ is C₁₋₃ alkyl;

R² is C₄₋₆ alkyl or C₅₋₆ cycloalkyl;

R³ is C₁₋₃ alkyl or aralkyl;

R⁴ is ##STR8## B is a bond or NH; R⁵ is hydrogen when B is NH; oraralkyl or ##STR9## A is a bond or --C═C--; n is 0-2; and

R⁶ is hydrogen or halo.

The most preferred compounds are those having the formula ##STR10##wherein R¹ is lower alkyl;

R² is n-butyl or cyclopentyl;

R³ is methyl;

R⁴ is ##STR11## R⁵ is hydrogen, aralkyl or ##STR12## R⁶ is hydrogen orhalo.

The compounds of the invention can be prepared by a basic reactionsequence, in which in the initial step an isovanillin derivative isreacted with a suitable R² group-containing derivative, to yield anisovanillin derivative intermediate with the appropriately substitutedhydroxy group: ##STR13## The latter is then reacted with malonic acid inthe presence of pyridine and piperidine to yield an intermediatecinnamic acid, which is then reacted with hydrazine hydrate to yield apyrazolidinone intermediate: ##STR14## Compounds in which R³ is loweralkyl can be prepared via the above-outlined route by the use of anappropriately substituted hydrazine hydrate: ##STR15## In an alternatesequence, the pyrazolidinone intermediate is reacted with sodium hydridefollowed by reaction with a suitable R³ derivative in an organicsolvent: ##STR16##

The R³ -substituted pyrazolidinone compounds are also intermediates forthe preparation of the various R⁴ -substituted pyrazolidinone derivativefinal products. The following flow chart illustrates the sequences usedto prepare the various compounds of the invention: ##STR17##

The compounds having a dihydro-pyrazoline ring are likewise preparedfrom the R³ substituted pyrazolidinone intermediates according to thefollowing sequence: ##STR18##

Of course, other methods of preparation, which will occur to thoseskilled in the art, may also be employed to prepare the compounds ofthis invention.

The starting materials used in the above-described preparative routesare commercially available, or can be made according to procedurestaught in the chemical literature.

Some compounds of the invention possess cis-trans isomerism andchirality and hence the compounds of the invention embrace not onlyracemic mixtures, but the individual isomers as well. The isomers aredesignated according to the E/Z-system and the R/S-system using thesequence rule.

The compounds of the invention, by virtue of their ability to inhibitthe enzyme 3':5'-cyclic AMP phosphodiesterase of pulmonary tissue (PDEIV) and to inhibit the influx of leukocytes into the lungs and pulmonarycavities, are bronchodilators and antiinflammatories, which are usefulin the treatment of acute and chronic bronchial asthma and itsassociated pathology.

Compounds of the invention which contain a basic nitrogen are capable offorming pharmaceutically acceptable salts, including the salts ofpharmaceutically acceptable organic and inorganic acids, such ashydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric,methanesulfonic, benzenesulfonic, acetic, citric, pumaric, maleic,succinic and the like.

When the compounds of the invention are employed in the treatment ofacute or chronic bronchial asthma, they can be formulated into oraldosage forms such as tablets, capsules and the like. The compounds canbe administered alone or by combining them with conventional carriers,such as magnesium carbonate, magnesium stearate, talc, sugar, lactose,pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, low melting wax, cocoa butter and the like.Diluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, tablet-disintegrating agents and the like may be employed. Thecompounds may also be injected parenterally, in which case they are usedin the form of a sterile solution containing other solutes, for example,enough saline or glucose to make the solution isotonic. Foradministration by inhalation or insufflation, the compounds may beformulated into an aqueous or partially aqueous solution, which can thenbe utilized in the form of an aerosol. The compounds may also beformulated into dry aerosol inhalation formulations.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Treatment will generally beinitiated with small dosages, less than the optimum dose of thecompound. Thereafter the dosage is increased until the optimum effectunder the circumstances is reached. In general, the compounds of theinvention are most desirably administered at a concentration that willgenerally afford effective results without causing any harmful ordeleterious side effects, and can be administered either as a singledose, or if desired, the dosage may be divided into convenient subunitsadministered at suitable times throughout the day.

The PDE IV inhibitory effects of the compounds of the invention may bedemonstrated by standard pharmacological procedures, which are describedmore fully in the examples given hereinafter. These proceduresillustrate the ability of the compounds of the invention to inhibit PDEIV isolated from canine trachea.

The following examples show the preparation and pharmacological testingof compounds within the invention.

EXAMPLE 1 5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3-pyrazolidinone

To a suspension of 3-cyclopentyloxy-4-methoxycinnamic acid (7.9 g, 30mmol) in toluene (25 ml) is added hydrazine hydrate (2.91 ml, 60 mmol).The reaction mixture is heated to 100° (bath temperature) for 24 hours.Toluene is partially removed and ether carefully added, and the productallowed to crystallize. The solid is filtered to give crude product (6g). A crystallization from chloroform-hexane gives the pure product (5g) m.p. 185°-186°. ¹ H NMR (CDCl₃) δ7.02 (1H, s, NH-CO), 6.88 (3H, m,arom), 4.79 (2H, m, carbinolic and benzylic), 4.28 (1H, m, NH), 3.84(3H, s, CH₃ O--), 2.79 (2H, d, --CH₂ CO), 1.9 (5H, m, cyclopentyl C--H),1.61 (3H, m, cyclopentyl C--H); IR (KBr), 3420, 3220, 3160, 2960, 1700,1660 cm⁻¹ ; MS m/z 276 (M)⁺.

Analysis for: C₁₅ H₂₀ N₂ O₃ : Calculated: C, 65.22; H, 7.29; N, 10.14.Found: C, 65.45; H, 7.30; N, 9.97.

EXAMPLE 25-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone

To a suspension of 3-cyclopentyloxy-4-methoxycinnamic acid (6.3 g, 24mmol) in toluene (15 ml), is added N-methylhydrazine (3.9 ml, 72 mmol).A precipitate is formed which slowly dissolves on warming. The mixtureis kept at 100°-105° (bath temperature) for 24 hours. The solvent isremoved under vacuum, and the residue partitioned between ethylacetate-water. The organic extract is dried and the solvent removed toyield crude product (7.6 g). Filtration through silica gel (100 g) in50% ethyl acetate/hexane and elution with 70-80% ethylacetate/hexanegives pure product (4 g) m.p. 115°-116°. ¹ H NMR (ME₂ SO-d₆); δ9.44 (1H,s, NHCO), 6.95 (1H, d, arom), 6.88 (2H, m, arom), 4.76 (1H, m,carbinolic), 3.81 (1H, t, benzylic), 3.71 (3H, s, CH₃ O), 2.76 (1H, 1,--CHCO), 2.36 (3H, s, CH₃ N), 2.33 (1H, m, --CHCO), 1.86 (2H, m,cyclopentyl--CH), 1.69 (4H, m, cyclopentyl --CH), 1.55 (2H, m,cyclopentyl --CH); IR (KBr); 3425, 3160, 2960, 1690, 1600 cm⁻¹. MS m/z;290 (M)⁺, 222 (M--C₅ H₈)⁺, 177 (M--(C₅ H₉ +CH₄ N₂))⁺.

Analysis for: C₁₆ H₂₂ N₂ O₃ : Calculated: C, 66.20; H, 7.58; N, 9.65.Found: C, 66.05; H, 7.74; N, 9.64.

EXAMPLE 35-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,2-dimethyl-3-pyrazolidinone,hydriodide

To a suspension of hexane-washed sodium hydride (0.176 g, 4.4 mmol, 60%suspension), in dry tetrahydrofuran (14 ml), is added5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-pyrazolidinone (1.1 g, 4 mmol).The suspension is stirred under nitrogen at room temperature. After 0.5hours, hydrogen evolution cases and the mixture becomes a turbidsolution. Methyl iodide (0.96 ml, 16 mmol) is added at room temperature,and the mixture stirred at room temperature, for 6 hours. The reactionis quenched with water, and the solvent is removed. The residue issuspended in water containing small amount of ethyl acetate. Afterstirring for about 20 minutes, the solid is filtered to yield crudeproduct (0.6 g). Two crystallizations from methanol-ether yielded a puresample (0.34 g) m.p. 192.5°-193°. ¹ H NMR (Me₂ SO-d₆) δ7.25 (2H, m,arom), 7.12 (1H, d, arom), 5.57 (1H, q, benzylic), 4.86 (1H, m,carbinolic), 3.8 (3H, s, O--CH₃) 3.76 (1H, m, --CHCO), 3.37 (3H, s, CH₃N), 3.19 (1H, q, CHCO), 2.94 (3H, s, --CH₃ N), 1.93 (2H, m, cyclopentyl--CH), 1.70 (4H, m, cyclopentyl--CH), 1.57 (2H, m, cyclopentyl --CH); IR(KBr), 3460, 2970, 1750, 1610 cm⁻¹ ; MS m/z; 305 (M+1)⁺, 245 (M--C₂ H₆N₂ +1)⁺.

Analysis for: C₁₇ H₂₄ N₂ O₃ : Calculated: C, 47.23; H, 5.83; N, 6.48.Found: C, 47.16; H, 5.61; N, 6.46.

EXAMPLE 45-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3-oxo-1-pyrazolidineacetic acidmethyl ester

To a suspension of hexane-washed sodium hydride (0.264 g, 6.6 mmol, 60%suspension) in tetrahydrofuran (10 ml) is added5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-pyrazolidinone (1.66 g, 6mmol). The mixture is kept at 50° for 30 minutes. To the turbidsolution, a solution of methyl bromoacetate (1.53 g, 10 mmol) intetrahydrofuran (5 ml) is added. The reaction mixture is kept at 60°-70°overnight. The solvent is removed and the residue partitioned betweenethyl acetate-water. The organic extract is dried, and the solventevaporated. The resulting product (2 g) is chromatographed on silica gel(60 g) in 40% ethyl acetate/hexane.

The desired product is eluted with 50-80% ethyl acetate-hexane to yieldthe product (1.12 g) m.p. 112°-113°. A crystallization fromchloroform-hexane yields pure product (0.93 g) m.p. 113°-116°. ¹ H NMR(Me₂ SO-d₆); δ9.47 (1H, s, NH), 6.98 (1H, d, arom), 6.89 (2H, m, arom),4.75 (1H, m, carbinolic) 4.26 (1H, m, benzylic), 3.7 (3H, s, CH₃ O),3.67 (1H, d, --CHCO), 3.6 (3H, s, O --CH₃), 3.45 (1H, d, --CHCO), 3.01(1H, q, --CHCO) 2.28 (1H, q, --CHCO); IR (KBr), 3230, 3140, 2930, 1750,1735, 1685 cm⁻¹ ; MS m/z 348 (M)⁺, 289 (M--COOCH3)⁺, 280 (M--C₅ H₉)⁺,221 (280--COOCH₃)⁺.

Analysis for: C₁₈ H₂₄ N₂ O₅ : Calculated: C, 62.06; H, 6.89; N, 8.04.Found: C, 61.45; H, 6.82; N, 7.99.

EXAMPLE 55-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3-oxo-1-pyrazolidinecarboxamide

A suspension of 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-pyrazolidinone(1.1 g, 4 mmol) in tetrahydrofuran is cooled to -30° C. Trichloroacetylisocyanate (0.59 ml, 5 mmol) is added and stirring continued for 45minutes, during which time the reaction mixture is warmed to roomtemperature. A saturated solution of ammonia in acetonitrile (5 ml) isadded and stirring continued overnight. The solvent is removed, and theresidue partitioned between ethyl acetate-water, dried and solvent isevaporated. The resulting residue (1.3 g) is put through silica gel (30g) in 60% ethyl acetate/hexane and the product eluted with 100% ethylacetate-20% methanol/ethyl acetate to yield pure compound (0.5 g). Twocrystallizations from methanol-ether give analytical sample m.p.115°-117°. ¹ H NMR (NMe₂ SO-d₆); δ6.96 (1H, d, arom), 6.87 (1H, d,arom), 6.82 (1H, q, arom), 6.47 (2H, b, NH₂), 5.49 (1H, d, benzylic),4.76 (1H, m, carbinolic), 3.72 (3H, s, O--CH₃), 3.16 (1H, q, --CHCO),2.18 (1H, d, --CHCO), 1.90 (2H, m, cyclopentyl --CH), 1.70 (4H, m,cyclopentyl --CH), 1.56 (2H, m, cyclopentyl --CH); IR (KBr), 3380, 3180,2940, 1660-1700 cm⁻¹. MS m/z 319 (M)⁺, 276 (M--CONH₂ +1)⁺, 208[M--(CONH₂ +C₅ H₈)+1]⁺.

Analysis for: C₁₆ H₂₁ N₃ O₄ : Calculated: C, 60.19; H, 6.58; N, 13.17.Found: C, 60.18; H, 6.12; N, 12.83.

EXAMPLE 65-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3-oxo-1-pyrazolidinecarboxylicacid methyl ester

To an ice cold suspension of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-pyrazolidinone (0.552 g, 2mmol) in tetrahydrofuran (3 ml) and triethylamine (0.3 ml, 2.2 mmol) isadded methyl chloroformate (0.2 ml, 2.6 mmol). The mixture is stirred at0° and allowed to reach room temperature. After 2 hours, more methylchloroformate (0.1 ml, 1.3 mmol) is added, and stirring continued fortwo more hours. The reaction is quenched with water, solvent is removed,and the residue partitioned between ethyl acetate-water. The organiclayer is dried, and solvent is removed to yield crude product (0.6 g).This is purified over silica gel (20 g) in 1:1 ethyl acetate-hexane. Theproduct is eluted with 60-80% ethyl acetate-hexane to give pure product(0.45 g). Crystallization from ethyl acetate-hexane gives analyticalsample (0.34 g) m.p. 106°-107°. ¹ H NMR (Me₂ SO-d₆) δ6.92 (1H, d, arom),6.8 (2H, m, arom), 5.4 (1H, q, benzylic), 4.74 (1H, d, --CHCO), 3.68(3H, s, O--CH₃), 3.64 (3H, s, O--CH₃), 3.29 (1H, q, --CHCO), 2.22 (1H,d, --CHCO), 1.86 (2H, m, cyclopentyl --CH), 1.7 (4H, m, cyclopentyl--CH), 1.54 (2H, m, cyclopentyl --CH). IR (KBr); 3570, 2930, 1680, 1710,cm⁻¹.

MS m/z; 334 (M)⁺, 266 (M--C₅ H₈)⁺.

Analysis for: C₁₇ H₂₂ N₂ O₅ : Calculated: C, 61.08; H, 6.59; N, 8.38.Found: C, 61.29; H, 6.79; N, 8.49.

EXAMPLE 75-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3-oxo-1-pyrazolidinecarboxylicacid

A solution of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-oxo-1-pyrazolidinecarboxylicacid methyl ester (0.696 g, 2 mmol) in methanol (4 ml) is mixed with2.5N sodium hydroxide solution (1.2 ml, 3 mmol). The reaction mixture iskept at 40° overnight. The solvent is removed, and the residuepartitioned between ethyl acetate/water, dried and the solventevaporated. Residue (0.7 g) is allowed to crystallize over ethylacetate/ether to yield solid (0.29 g) m.p. 137°-139°. A crystallizationfrom ethyl acetate/ether gives analytical sample m.p. 136°-7°. ¹ H NMR(Me₂ SO-d₆); δ9.38 (1H, broad, NH), 7.02 (1H, d, arom), 6.89 (2H, m,arom), 4.75 (1H, m, carbinolic), 4.27 (1H, q, benzylic), 3.72 (3H, s,O--CH₃), 3.60 (1H, d, --CHCO), 3.37 (1H, d, --CHCO), 3.04 (1H, q,--CHCO), 2.25 (1H, q, --CHCO), 1.88 (2H, m, cyclopentyl --CH), 1.70 (4H,m, cyclopentyl --CH), 1.56 (2H, m, cyclopentyl --CH), IR (KBr), 3210,2940, 2450, 1710, 1630, 1510 cm⁻¹.

MS m/z, 335 (M+1)⁺.

Analysis for: C₁₇ H₂₂ N₂ O₅ : Calculated: C, 61.08; H, 6.59; N, 8.38.Found: C, 61.18; H, 6.68; N, 8.02.

EXAMPLE 83-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-pyrazolidinecarboxamide,hydrochloride

5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (0.58g, 2 mmol) is dissolved in tetrahydrofuran (3 ml), and the solution iscooled to -30° C. Trichloroacetyl isocyanate (0.3 ml, 2.5 mmol) isgradually added, and the reaction mixture is stirred and allowed toreach room temperature, during 1 hour. A saturated solution of ammoniain acetonitrile (7 ml) is added to the reaction and stirring continuedfor three hours. The solvent is removed, and the residue is partitionedbetween ethyl acetate/water, dried and the solvent is evaporated. Theresidue (0.9 g) is put on silica gel (13 g) in 20% ethyl acetate/hexaneand the product is eluted with 40-50% ethyl acetate/hexane, to yieldpure product (0.67 g), as a colorless oil. The product is suspended inether (˜3 ml) and 2N methanolic HCl (3 ml) added to it and the mixtureis stirred for 10 minutes. The solvent is removed, the residuetriturated with ether, and filtered to yield a white solid (0.61 g). Acrystallization from methanol/ether gives analytically pure material(0.42 g) m.p. 142°-143°. ¹ H NMR (Me₂ SO-d₆); δ7.39 (2H, m NH₂), 6.97(1H, d, arom), 6.91 (1H, d, arom), 6.84 (1H, q, arom), 4.71 (1H, m,carbinolic), 4.36 (1H, m, benzylic), 3.70 (3H, s, O--CH₃), 3.64 (1H, m,--CHCO), 2.72 (3H, s, N--CH₃), 2.64 (1H, m, --CHCO), 1.85 (2H, m,cyclopentyl --CH), 1.67 (4H, m, cyclopentyl --CH), 1.54 (2H, m,cyclopentyl --CH); IR (KBr), 3380, 3250, 2960, 2550, 1790, 1730, 1590cm⁻¹.

MS m/z, 334 (M)⁺, 291 (M--CONH₂ +1)⁺

Analysis for: C₁₇ H₂₃ N₃ O₄.HCl: Calculated: C, 55.21; H, 6.47; N,11.37. Found: C, 55.12; H, 6.43; N, 11.30.

EXAMPLE 93-[3-(Cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-N-methyl-1-pyrazolidinecarboxamide,hemihydrate

5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (0.51g, 1.75 mmol) is suspended in tetrahydrofuran (3 ml). Methyl isocyanate(0.13 ml, 2.2 mmol) is slowly added to the mixture. The reaction isstirred overnight. More methyl isocyanate (0.065 ml, 1.1 mmol) is added,and the mixture is stirred for 4 hours. The solvent is removed, and theresidue partitioned between ethyl acetate/water, dried and solvent isevaporated. The residue (0.7 g) is put through silica gel (20 g) in 30%ethyl acetate/hexane. The product is eluted with 40 to 60% ethylacetate/hexane to give pure sample (0.58 g) as pale brown oil. The oil(0.3 g) is taken in ether (4 ml) and 2N methanolic HCl (2 ml) added toit. The mixture is stirred for 10 minutes and the solvent is removed.The residue is triturated with ether and filtered to give solid (0.4 g).A crystallization from methanol/ether gives pure sample (0.23 g) m.p.145°-7° C. Drying for 3 days under vacuum at 60° C. yields a low meltingsolid (0.2 g), m.p. 65°-68° C. ¹ H NMR (Me₂ SO-d₆); δ7.81 (1H, q, NH),6.94 (1H, d, arom), 6.89 (1H, d, arom), 6.83 (1H, q, arom), 4.73 (1H, m,carbinolic), 4.36 (1H, m, benzylic), 3.71 (3H, d, O--CH₃), 3.63 (1H, m,--CHCO), 2.73 (3H, s, N--CH₃), 2.68 (3H, d, N--CH₃), 2.62 (1H, m, --CHCO), 1.84 (2H, m, cyclopentyl --CH), 1.62 (6H, m, cyclopentyl --CH).

MS m/z 290 (M--CONHCH₃ +1)⁺

Analysis for: C₁₈ H₂₅ N₃ O₄.0.5 H₂ O: Calculated: C, 60.67; H, 7.30; N,11.8. Found: C, 60.75; H, 7.28; N, 11.7.

EXAMPLE 105-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,2-dihydro-1-methyl-3H-pyrazol-3-one

To a magnetically-stirred solution of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (68.88mmol, 20.0 g) in dry tetrahydrofuran (300 mL) at 0° C. is added, viacannula, a suspension of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ,68.88 mmol, 15.64 g) in 200 mL dry tetrahydrofuran. The resultingheterogeneous mixture is allowed to warm slowly from 0° C. to roomtemperature overnight. The solvent is removed in vacuo and thereddish-brown residue is triturated with methylene chloride. Theundissolved yellow solid is removed via suction and discarded. Thefiltrate is concentrated in vacuo to produce a brownish foam which ispurified by flash chromatography (SiO₂ : gradient ranging from 15% ethylacetate/methylene chloride to 30% ethyl acetate/methylene chloride).Concentration in vacuo affords a light tan solid which is driedovernight in vacuo at 50° C. to give the title compound (22.54 mmol,6.50 g., 32.7%). ¹ H NMR (DMSO-d₆, 400 MHz) δ9.58 (s, 1H); 6.98 (m, 3H);5.53 (s, 1H); 4.83 (m, 1H); 3.77 (s, 3H); 3.60 (s, 3H); 1.90 (m, 2H);1.70 (m, 4H); 1.55 (m, 2H). IR (KBr, cm⁻¹) 3440, 2950, 2830, 1950, 1600,1517, 1483, 1310, 1252, 1235, 1165, 1135, 1020, 770.

MS (EI, m/e(%)) 228 (6, M+); 220 (38); 185 (56); 168 (28); 153 (29); 143(33); 127 (100); 115 (38); 77 (19).

Analysis for: C₁₆ H₂₀ N₂ O₃ : Calculated: C, 66.64; H, 6.99; N, 9.72.Found: C, 66.23; H, 6.62; N, 9.53.

EXAMPLE 113-[3-(cyclopentyloxy)-4-methoxyphenyl]-2,5-dihydro-2-methyl-5-oxo-1H-pyrazole-1-carboxamide

To a 0° C. solution of phosgene (8.75 mmol, 4.61 mL; 1.9M solution intoluene) in dry tetrahydrofuran (30 mL) is added5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,2-dihydro-1-methyl-3H-pyrazol-3-one(7.0 mmol, 2.02 g) in dry tetrahydrofuran (15 mL) dropwise over 20minutes. The resulting cloudy solution is stirred at 0° C. for 10minutes and at room temperature for 1 hour after which a homogenoussolution is obtained. The reaction mixture is cooled to 0° C. andhexamethyldisilazane (17.5 mmol, 2.82 g; 3.64 mL) in dry tetrahydrofuran(15 mL) is added in one portion. The resulting suspension is stirred atroom temperature for 1 hour and then the volatiles are removed in vacuo.The residue is partitioned between 2% aqueous acetic acid (200 mL) andethyl acetate (200 mL) and the aqueous phase is extracted with ethylacetate (150 mL). The combined organic layers are washed with H₂ O (100mL), dried (Na₂ SO₄), and concentrated in vacuo to afford a tan solid.This material is triturated with ether and dried in vacuo for 1 hour at60° C. to give the title compound as a white solid (1.80 g; 78%). ¹ HNMR (DMSO-d₆, 400 MHz) δ7.23 (br s, 1H); 7.02 (m, 3H); 6.92 (br s, 1H);6.08 (s, 1H); 4.86 (m, 1H); 3.78 (s, 3H); 3.72 (s, 3H); 1.88 (m, 2H);1.70 (m, 4H); 1.56 (m, 2H). IR (KBr, cm⁻¹) 3400, 3300, 3200, 2950, 1760,1500, 1330, 1250, 1130.

MS (+FAB, m/e (%)) 332 (90, M+H); 289 (100); 220 (40).

Analysis for: C₁₇ H₂₁ N₃ O₄ : Calculated: C, 61.62; H, 6.39; N, 12.68.Found: C, 61.67; H, 6.35; N, 12.30.

EXAMPLE 123-[3-(cyclopentyloxy)-4-methoxyphenyl]-2,5-dihydro-2-methyl-5-oxo-N-(2-pyridinylmethyl)-1H-pyrazole-1-carboxamide

In the same manner as Example 11 above,5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,2-dihydro-1-methyl-3H-pyrazol-3-one(0.8 mmol, 0.230 g) in tetrahydrofuran (5 mL) was reacted with phosgene(1.00 mmol, 0.526 mL; 1.9M solution in toluene) in tetrahydrofuran (5mL) and to this solution was added 2-(methylamino)pyridine (1.00 mmol,0.108 g; 0.103 mL) and pyridine (2.00 mmol, 0.158 g; 0.162 mL) intetrahydrofuran (5 mL) in one portion at 0° C. The resulting yellowsuspension is stirred for 1 hour at room temperature, and the resultingdark red reaction mixture is partitioned between ethyl acetate (100 mL)and water (100 mL). The aqueous phase is extracted with ethyl acetate(100 mL), the combined organic layers are washed with water (100 mL),dried (Na₂ SO₄), and concentrated in vacuo to afford a dark brownresidue. This material is purified by flash chromatography (SiO₂ : 1)methylene chloride; 2) 5% ethyl acetate/methylene chloride; 3) 10% ethylacetate/methylene chloride) to give a light brown oil. Treatment withether and ethanolic HCl yields the title compound as the dihydrochloridesalt which is dried in vacuo at 60° C. for 2 hours (100 mg; 25%). ¹ HNMR (DMSO-d₆, 400 MHz) δ8.75 (d, 1H, J=5 Hz); 8.62 (t, 1H, J=5 Hz); 8.33(t, 1H, J=7 Hz); 7.76 (m, 2H); 7.02 (m, 3H), 6.13 (s, 1H); 4.86 (m, 1H);4.58 (d, 2H, J=6 Hz); 3.78 (s, 3H); 3.73 (s, 3H); 1.88 (m, 2H); 1.72 (m,4H); 1.55 (m, 2H). IR (KBr, cm⁻¹) 3400, 3225, 2950, 2575, 2400, 1780,1750, 1615, 1395, 1360, 1255.

MS (+FAB, m/e (%)) 423 (10, M+H); 289 (100); 135 (40).

Analysis for: C₂₃ H₂₆ N₄ O₄.2 HCl.0.35 H₂ O: Calculated: C, 55.06; H,5.77; N, 11.17. Found: C, 55.08; H, 5.74; N, 11.20.

EXAMPLE 13(S)-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-N-[1-(1-naphthalenyl)ethyl]-5-oxo-1-pyrazolidinecarboxamide

To a stirred solution of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (2.0mmol, 0.580 g) in dry tetrahydrofuran (10 mL) at 0° C. is added neat(S)-(+)-1-(1-naphthyl)ethyl isocyanate in one portion. The resultingcolorless solution is stirred at room temperature overnight and thevolatiles are removed in vacuo. The residue is partitioned between ethylacetate (200 mL) and water (200 mL) and the aqueous phase is extractedwith ethyl acetate (1×100 mL). The combined organic layers are dried(Na₂ SO₄) and concentrated in vacuo. The residue is purified by flashchromatography (SiO₂ : 1) methylene chloride; 2) 2% ethylacetate/methylene chloride; 3) 5% ethyl acetate/methylene chloride) toafford the diastereomerically-pure products as white solids. In thisexperiment, one obtains 0.450 g (46%) of high R_(f) diastereomer and0.460 g (47%) of low R_(f) diastereomer.

A) high R_(f) diastereomer

¹ H NMR (DMSO-d₆, 400 MHz) δ8.38 (d, 1H, J=8 Hz); 8.12 (d, 1H, J=8 Hz);7.96 (dd, 1H, J=8, 1.5 Hz); 7.85 (t, 1H, J=5 Hz); 7.55 (m, 2H), 7.49 (d,2H, J=4.5 Hz); 6.97 (d, 1H, J=2 Hz); 6.89 (d, 1H, J=8 Hz); 6.84 (dd, 1H,J=8, 2 Hz); 5.71 (p, 1H, J=7 Hz); 4.72 (m, 1H); 4.38 (m, 1H); 3.72 (s,3H); 3.65 (m, 1H); 2.72 (s, 3H); 2.70 (m, 1H); 1.88 (m, 2H); 1.67 (m,4H); 1.55 (m, 5H). IR (KBr, cm⁻¹) 3400, 3300, 2950, 1715, 1700, 1505,1300, 1250, 1220, 770.

MS (+FAB, m/e (%)) 488 (10, M+H); 313 (20); 291 (100); 177 (25); 155(90).

Analysis for: C₂₉ H₃₃ N₃ O₄ : Calculated: C, 71.44; H, 6.82; N, 8.62.Found: C, 71.10; H, 6.89; N, 8.26.

Optical Rotation (MeOH, 10.1 mg/mL) α=-0.053°|α|_(D) =-5.2°

B) low R_(f) diastereomer

¹ H NMR (DMSO-d₆, 400 MHz) δ8.44 (d, 1H, J=8 Hz); 8.12 (d, 1H, J=8 Hz);7.95 (d, 1H, J=8 Hz); 7.83 (d, 1H, J=8 Hz); 7.55 (m, 2H); 7.44 (m, 2H);6.90 (d, 1H, J=2 Hz); 6.84 (d, 1H, J=8 Hz); 6.79 (dd, 1H, J=8, 2 Hz);5.75 (p, 1H, J=7 Hz); 4.50 (m, 1H); 4.38 (m, 1H); 3.72 (m, 1H); 3.68 (s,3H); 2.76 (s, 3H); 2.63 (m, 1H); 1.70 (m, 1H); 1.57 (d, 3H, J=7 Hz);1.49 (m, 5H); 1.34 (m, 1H), 1.23 (m, 1H). IR (KBr, cm⁻¹) 3400, 3300,2960, 1715, 1965, 1505, 1250, 1220.

MS (CI, m/e (%)) 488 (15, M+H); 445 (60); 291 (100); 197 (95); 155 (98).

Analysis for: C₂₉ H₃₃ N₃ O₄ : Calculated: C, 71.44; H, 6.82; N, 8.62.Found: C, 71.21; H, 6.81; N, 8.55.

Optical Rotation (MeOH, 9.2 mg/mL) α=+0.837°|α|_(D) =+91.0°

EXAMPLE 14N-butyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-1-pyrazolidinecarboxamidehydrochloride

5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (2.06mmol, 0.600 g) is dissolved in dry chloroform (10 mL) in a N₂atmosphere. To this is added dropwise at room temperature butylisocyanate (5.15 mmol; 0.583 mL) neat. The sample is heated to refluxfor 4 hours at which time TLC shows no starting material. The sample isevaporated to yield a clear oil which is dissolved in ether. To thissolution is added ethanolic HCl and the sample is stirred for 15 minutesand evaporated in vacuo to afford a solid which is recrystallized fromchloroform and hexane to give the title compound as a white solid (0.495mg; 56%) m.p.: 115°-122° C. (dec) ¹ H NMR (DMSO-d₆, 400 MHz) δ8.3 (s,1H); 7.91 (t, 3H, J=5.7 Hz); 6.95 (d, 1H, J=1.3 Hz); 6.89 (d, 1H, J=8.3Hz); 6.81 (dd, 1H, J=8.3, 1.6 Hz); 4.68 (m, 1H); 4.35 (d, 1H, J=5.6 Hz);3.69 (s, 3H); 3.15 (m, 2H); 2.73 (s, 3H); 1.84 (m, 2H); 1.68 (m, 3H);1.54 (m, 2H); 1.40 (m, 2H); 1.23 (m, 3H); 0.85 (t, 2H, J=7.3 Hz). IR(KBr, cm⁻¹) 1760

MS (EI, m/e) 389 (M+); 290.

Analysis for: C₂₁ H₃₁ N₃ O₄.HCl: Calculated: C, 59.22; H, 7.57; N, 9.86.Found: C, 58.92; H, 7.68; N, 9.72.

EXAMPLE 153-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-ethyl-2-methyl-5-oxo-1-pyrazolidinecarboxamidehydrochloride, hydrate

Following the procedure of Example 14 and using ethyl isocyanate, yields40% of title compound. m.p.: 106°-111° C. ¹ H NMR (DMSO-d₆, 400 MHz)δ7.91 (t, 3H, J=5.7 Hz); 6.95 (d, 1H, J=1.6 Hz); 6.89 (d, 1H, J=8.3 Hz);6.83 (dd, 1H, J=8.3, 1.6 Hz); 4.69 (m, 1H); 4.36 (d, 1H, J=6 Hz); 3.69(s, 3H); 3.17 (m, 2H); 2.72 (s, 3H); 1.68 (m, 2H); 1.66 (m, 3H); 1.53(m, 2H). IR (KBr, cm⁻¹) 1770, 1720.

MS (EI, m/e) 361 (M+); 290.

Analysis for: C₁₉ H₂₈ N₃ O₄.HCl.H₂ O: Calculated: C, 54.73; H, 7.49; N,10.07. Found: C, 54.89; H, 7.18; N, 10.05.

EXAMPLE 163-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-N-phenyl-1-pyrazolidinecarboxamide hydrochloride

Following the procedure of Example 14 and using phenyl isocyanate,yields 0.850 g (93%) of title compound as a white powder. m.p.:134°-142° C. (dec) ¹ H NMR (DMSO-d₆, 400 MHz) δ9.95 (s, 1H); 7.50 (d,2H, J=9 Hz); 7.32 (t, 2H, J=7 Hz); 7.08 (t, 1H, J=7 Hz); 7.00 (s, 1H);6.90 (m, 2H); 4.70 (m, 1H); 3.69 (s, 3H); 2.80 (m, 4H); 1.82 (m, 2H);1.64 (m, 3H); 147 (m, 2H). Br, cm⁻¹) 1760, 1730.

MS (+FAB, m/e) 410 (M+H).

EXAMPLE 173-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-N-(phenylmethyl)-1-pyrazolidinecarboxamidehydrochloride

Following the procedure of Example 14 and using benzyl isocyanate,yields 0.275 g (35%) of title compound as a light yellow solid. m.p.:67°-72° C. (dec) ¹ H NMR (DMSO-d₆, 400 MHz) δ8.36 (m, 1H); 7.26 (m, 5H);6.95 (s, 1H); 6.86 (m, 2H); 4.65 (m, 1H); 4.37 (m, 3H); 3.70 (s, 3H);2.74 (s, 3H), 1.80 (m, 2H); 1.64 (m, 3H); 1.50 (m, 2H). IR (KBr, cm⁻¹)1760, 1720.

MS (EI, m/e) 423 (M+).

Analysis for: C₂₄ H₂₉ N₃ O₄.0.5 HCl: Calculated: C, 65.68; H, 6.60; N,9.49. Found: C, 65.68; H, 6.76; N, 9.36.

EXAMPLE 18N-cyclohexyl-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-1-pyrazolidinecarboxamide hydrochloride

Following the procedure of Example 14 and using cyclohexyl isocyanate,yields 0.270 g (16%) of title compound as a white solid. mp: 105°-110°C. (dec) ¹ H NMR (DMSO-d₆, 400 MHz) δ7.88 (d, 1H, J=7 Hz); 6.94 (d, 1H,J=2 Hz); 6.89 (d, 1H, J=8 Hz); 6.81 (dd, 1H, J=8, 2 Hz); 4.67 (m,1H);4.36 (d, 1H, J=7 Hz); 3.69 (s, 3H); 2.48 (m, 4H); 1.70 (m, 13H); 1.26(m, 5H). IR (KBr, cm⁻¹) 1760, 1720.

MS (EI, m/e) 416 (M+).

Analysis for: C₂₃ H₃₃ N₃ O₄.0.5 HCl: Calculated: C, 63.68; H, 7.66; N,9.68. Found: C, 63.06; H, 7.77; N, 9.48.

EXAMPLE 193-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-(4-methoxyphenyl)-2-methyl-5-oxo-1-pyrazolidinecarboxamide

Following the procedure of Example 14 and using 4-methoxyphenylisocyanate, yields 0.525 g (70%) of title compound as a white solid.m.p.: 123°-125° C. ¹ H NMR (CDCl₃, 400 MHz) δ9.98 (s, 1H); 7.42 (d, 2H,J=9 Hz); 7.26 (s, 1H); 7.00 (d, 1H, J=2 Hz); 6.87 (m, 3H); 4.78 (m, 1H);4.39 (br s, 1H); 3.82 (s, 3H); 3.79 (s, 3H); 1.83 (m, 6H); 1.58 (m, 2H).IR (KBr, cm⁻¹) 1720, 1710.

MS (+FAB, m/e) 440 (M+H).

Analysis for: C₂₄ H₂₉ N₃ O₅ : Calculated: C, 65.59; H, 6.65; N, 9.56.Found: C, 65.26; H, 6.72; N, 9.49.

EXAMPLE 203-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-[(4-fluorophenyl)methyl]-2-methyl-5-oxo-1-pyrazolidinecarbothioamide

Following the procedure of Example 14 above, 4-fluorobenzylisothiocyanate yielded 0.146 g (19%) of title compound as a white solid.mp: 48°-51° C. ¹ H NMR (CDCl₃, 400 MHz) δ10.38 (s, 1H); 7.28 (m, 2H);7.18 (s, 1H); 7.02 (t, 2H, J=8 Hz); 6.84 (m, 2H); 4.82 (d, 3H, J=5 Hz);4.43 (m, 1H); 3.83 (s, 3H); 1.88 (m, 5H); 1.60 (m, 3H). IR (film, cm⁻¹)1700.

MS (+FAB, m/e) 458 (M+H).

Analysis for: C₂₄ H₂₈ FN₃ O₃ S: Calculated: C, 63.00; H, 6.17; N, 9.18.Found: C, 63.13; H, 6.25; N, 9.45.

EXAMPLE 213-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-[(4-methoxyphenyl)methyl]-2-methyl-5-oxo-1-pyrazolidinecarbothioamide

Following the procedure of Example 14 and using 4-methoxybenzylisothiocyanate, yielded 0.489 g (63%) of title compound as a yellowsolid. m.p.: 52°-55° C. ¹ H NMR (DMSO-d₆, 400 MHz) δ10.28 (m, 1H); 7.22(d, 2H, J=9 Hz); 7.13 (d, 1H, J=2 Hz); 6.88 (m, 4H); 4.70 (m, 2H); 4.48(d, 1H, J=8 Hz); 3.70 (s, 3H); 3.69 (s, 3H); 1.72 (m, 7H). IR (KBr,cm⁻¹) 1700.

MS (+FAB, m/e) 470 (M+H).

Analysis for: C₂₄ H₃₁ N₃ O₄ S: Calculated: C, 63.00; H, 6.83; N, 9.18.Found: C, 63.94; H, 6.53; N, 8.66.

EXAMPLE 223-[3-(cyclopentyloxy)-4-methoxyphenyl]-N-(4-fluorophenyl)-2-methyl-5-oxo-1-pyrazolidinecarboxamide

Following the procedure of Example 14 above, 4-fluorophenyl isocyanateyielded 0.375 g (43%) of title compound as white needles. m.p.:123°-124° C. ¹ H NMR (CDCl₃, 400 MHz) δ10.06 (s, 1H); 7.50 (m, 2H); 7.26(s, 1H); 7.02 (m, 3H); 6.86 (m, 2H); 4.77 (m, 1H); 4.39 (m, 1H); 3.82(s, 3H); 3.50 (m, 1H); 2.90 (m, 4H); 1.85 (m, 5H), 1.58 (m, 3H). IR(KBr, cm⁻¹) 1720, 1710. MS (CI, m/e) 428 (M+H).

Analysis for: C₂₃ H₂₅ FN₃ O₄ : Calculated: C, 64.78; H, 5.91; N, 9.85.Found: C, 64.45; H, 6.20; N, 9.67.

EXAMPLE 233-[3-(cyclopentyloxy)-4-methoxyphenyl]-5-oxo-2-(phenylmethyl)-1-pyrazolidinecarboxamide

3-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-(phenylmethyl)-pyrazolidinone(0.994 gms, 2.71 mmol) is dissolved in tetrahydrofuran (4.07 mls) andcooled to 0° C. under N₂. Trichloroacetyl isocyanate (0.421 mls, 3.39mmol, 1.25 eq) is added and the solution is stirred. After one hour theice bath is removed, and saturated ammonia in acetonitrile (22.5 mls) isadded at room temperature. After two hours, solvents are removed invacuo. The residue is diluted with ethyl acetate (45 mls) and washedwith water (45 mls). The aqueous layer is extracted with ethyl acetate(45 mls) and the combined organics are dried over Na₂ SO₄. The crudeproduct is chromatographed [hexane, 4:1, 3:2, 1:1 (hexane:ethylacetate)] and recrystallized (methylene chloride/hexane) to afford thetitle compound as a white solid (0.747 gms, 1.82 mmol, 67%, m.p.148°-149° C.) ¹ H NMR (DMSO-d₆, 400 MHz) δ7.52 (s, 1H), 7.50-6.77 (m,8H), 7.41 (s, 1H), 4.63 (m, 1H), 4.27 (m, 1H), 4.16 (m, 2H), 3.67 (s,3H), 3.58 (m, 1H), 2.49 (m, 2), 1.86-1.53 (m, 8H). IR(KBr, cm⁻¹) 3380,3360, 1725(C═O), 1700(C═O).

MS(FAB), m/z 410 (MH⁺).

Analysis for: C₂₃ H₂₇ N₃ O₄ : Calculated: C, 67.46; H, 6.65; N, 10.26.Found: C, 67.41; H, 6.67; N, 10.32.

EXAMPLE 243-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-N-(3-pyridinylmethyl)-1-pyrazolidinecarboxamide

To a -15° C. solution of phosgene (4.50 mmol, 2.30 mL; 1.9M solution intoluene) in dry tetrahydrofuran (8 mL) is added neat triethylamine (4.50mmol, 0.450 g; 0.620 mL) and the resulting suspension is stirred at -15°C. for 10 minutes. To this suspension is added 3-picolylamine (4.50mmol, 0.490 g; 0.460 mL) and triethylamine (4.50 mmol, 0.450 g; 0.620mL) in dry tetrahydrofuran (10 mL) in one portion and the reactionmixture is stirred at -15° C. for 30 minutes. Subsequently,5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (3.0mmol, 0.870 g) in dry tetrahydrofuran (7 mL) is added at -15° C. and thereaction mixture is allowed to warm to room temperature overnight. Thereaction is quenched with water (20 mL), the volatiles removed in vacuo,and the residue partitioned between ethyl acetate (150 mL) and water(150 mL). The organic layer is dried (Na₂ SO₄) and concentrated in vacuoto give a tan solid. This material is purified by flash chromatography(SiO₂ :1) 50% ethyl acetate/hexane; 2) 100% ethyl acetate; 3) 5%methanol/ethyl acetate) to give a mixture of starting material andproduct which is triturated with ether. The title compound is isolatedas a white solid (0.158 g; 12%). Also isolated is a mixture of startingpyridazone and title compound (0.511 g). ¹ H-NMR (DMSO-d₆, 400 MHz)δ8.45 (m, 3H); 7.65 (dt, 1H, J=8.0, 1.6 Hz); 7.22 (ddd, 1H, J=8.0, 5.0,0.7 Hz); 6.94 (d, 1H, J=2.0 Hz); 6.88 (d, 1H, J=8.0 Hz); 6.82 (dd, 1H,J=8.0, 2.0 Hz); 4.63 (m, 1H); 4.38 (m, 3H); 3.70 (s, 3H); 3.65 (m, 1H);2.74 (s, 3H); 2.65 (m, 1H); 1.79 (m, 2H); 1.63 (m, 4H); 1.49 (m, 2H). IR(KBr, cm⁻¹) 3420, 3320, 2950, 1730, 1715, 1530, 1515, 1235, 1135.

MS (CI, m/e (%)) 425(M⁺, 55), 291(100), 135(99).

Analysis for: C₂₃ H₂₈ N₄ O₄ : Calculated: C, 65.08; H, 6.65; N, 13.20.Found: C, 64.75; H, 6.67; N, 13.14.

EXAMPLE 255-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(3-pyridinylmethyl)-3-pyrazolidinonehydrochloride dihydrate

Sodium hydride (0.14 g of a 60% dispersion in mineral oil, 3.5 mmol, 1.0equiv) is added to a solution of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (1.0 g,3.4 mmol, 1.0 equiv) in anhydrous N,N-dimethylformamide (20 mL), and thereaction mixture is stirred at room temperature for 20 minutes.3-Picolyl chloride (0.54 g, 4.2 mmol, 1.2 equiv) inN,N-dimethylformamide is added dropwise and the resulting mixture isstirred at room temperature for 48 hours. The solvent is removed invacuo and the residue is taken up in methylene chloride, washed oncewith 1N sodium hydroxide, once with brine, and then dried (Na₂ SO₄).Chromatography on silica gel with hexanes/ethyl acetate gives 0.7 g ofan oil, which is dissolved in 2N HCl (0.9 mL) and methanol. Evaporationand recrystallization from ethyl acetate and methylene chloride yields0.16 g (12%) of a white solid identified as 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(3-pyridinylmethyl)-3-pyrazolidinonehydrochloride dihydrate: mp 182°-186° C. ¹ H NMR (d⁶ -DMSO, 400 MHz)δ8.83 (d, J=5.0 Hz, 1H), 8.80 (s, 1H), 8.33 (d, J=8 Hz, 1H), 7.93 (dd,J=5, 8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 6.76 (d, J=2 Hz, 1H), 6.68 (d, J=8Hz, 1H), 4.96 (AB quartet, J=16 Hz, 1H), 4.62 (m, 1H), 4.59 (AB quartet,J=16 Hz, 1H), 4.06 (m, 1H), 3.70 (s, 3H), 3.11 (m, 1H), 2.69 (m, 1H),2.53 (s, 3H), 1.87-1.48 (m, 8H). IR (KBr, cm⁻¹) 3420, 3005, 2942, 2920,2580, 2260, 1725, 1600, 1540, 1510, 1460, 1355, 1335, 1242, 1157.

MS, m/e (relative intensity) 381 (M⁺, 55), 289 (100), 221 (54), 150(58).

Analysis for: C₂₂ H₃₂ ClN₃ O₅ : Calculated: C, 58.34; H, 7.12; N, 9.27.Found: C, 57.72; H, 6.43; N, 9.05.

EXAMPLE 265-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-heptyl-1-methyl-3-pyrazolidinonehydrochloride

Following the general procedure of Example 25, the reaction ofbromoheptane (0.65 mL, 4.1 mmol, 1.2 equiv) in dimethylformamide givesafter chromatography on silica gel with hexanes/ethyl acetate, 0.7 g ofan oil, which is dissolved in 2N HCl (0.9 mL) and methanol. Evaporationand recrystallization from ethyl acetate and hexanes yields 0.56 g (43%)of a white solid identified as5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-heptyl-1-methyl-3-pyrazolidinonehydrochloride: mp 113°-117° C.

¹ H NMR (d⁶ -DMSO, 400 MHz) δ6.96 (s, 1H), 6.89 (m, 2H), 4.74 (m, 1H),4.06 (m, 1H), 3.71 (s, 3H), 3.54 (dt, J=7, 14 Hz, 1H), 3.10 (m, 1H),3.03 (dd, J=7, 16 Hz, 1H), 2.52 (s, 3H), 2.50 (m, 1H), 1.84 (m, 2H),1.70 (m, 4H), 1.61-1.42 (m, 4H), 1.18 (m, 8H), 0.83 (t, J=7 Hz, 3H). IR(KBr, cm⁻¹) 3420, 2940, 2919, 2840, 2220, 1730, 1710, 1600, 1582, 1510,1440, 1260, 1160, 1140.

MS m/e (relative intensity) 388 (M⁺, 100), 320 (16), 177 (85), 150 (59).

Analysis for: C₂₃ H₃₇ ClN₂ O₃ : Calculated: C, 65.00; H, 8.77; N, 6.59.Found: C, 65.01; H, 8.66; N, 6.53.

EXAMPLE 272-[(5-bromo-3-pyridinyl)methyl]-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinonehydrochloride A. 5-bromo-3-(bromomethyl)pyridine

To a solution of 5-bromo-3-pyridylmethanol [see Kauffman, T., andFischer, H.(1973) Chem. Ber. 106, 220-227.] (0.525 gms, 2.79 mmol) inmethylene chloride (2.6 mls) at 0° C. is added pyridine (0.26 mls, 3.21mmol) then mesyl chloride (0.25 mls, 3.23 mmol). After stirring 2 hours,K₂ CO₃ (0.88 gms, 6.37 mmol) is added. Stirring is continued for onehour and the ice bath is removed. The mixture is diluted with methylenechloride and washed with saturated aqueous NaHCO₃. The organic layer isdried over Na₂ SO₄ and evaporated to a viscous residue (>0.6 gms). Theresidue is dissolved in methylene chloride (8.8 mls) and tetrahydrofuran(4.4 mls) without further purification or characterization. LiBr powder(0.46 gms, 5.53 mmol) is introduced and the reaction is immersed in anoil bath (80° C.) for one hour. The crude mixture is concentrated andresolvated with ethyl acetate. Any remaining residue is pulverized andrinsed with methylene chloride. Combined organics are dried over Na₂ SO₄and evaporated to a solid (0.7 gms, 2.79 mmol; 100%). ¹ H NMR (CDCl₃,300 MHz) δ8.65 (s, 1H), 8.55 (s, 1H), 7.90 (s, 1H), 4.45 (s, 2H).

B. 2-[(5-bromo-3-pyridinyl)methyl]-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinonehydrochloride

To a solution of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (0.81gms, 2.79 mmol) in dimethylformamide (16 mls) is added NaH (0.11 gms,60%, 2.75 mmol) at room temperature. After stirring 15 minutes,5-bromo-3-(bromomethyl)pyridine (0.70 gms, 2.79 mmol) is added and thesolution is immersed in an oil bath (75° C.). After 20 hours,dimethylformamide is removed in vacuo. The crude material (0.9 gms) ischromatographed (1:1 hexane:ethyl actate, then 2:1 ethyl acetate:hexane)and dissolved in methanol (10 mls), then 0.7 mls 2N HCl is added. Theresulting mixture is evaporated and resolvated (methanol) twice to yieldthe salt (0.65 gms, 1.31 mmol, 47%). Recrystallization in methylenechloride/ethyl acetate affords 0.12 gms of solid title compound (mp163°-164°). ¹ H NMR (DMSO-d₆, 400 MHz) δ8.60 (s, 1H), 7.80 (s, 1H), 6.80(d, J=8.2 Hz, 1H), 6.75 (s, 1H), 6.65 (d, J=9.2 Hz, 1H), 4.80 (d, J=16.0Hz, 1H), 4.55 (m, 1H), 4.35 (d, J=16.1 Hz, 1H), 4.05 (m, 1H), 3.70 (s,3H), 3.10 (m, 2H), 2.55 (s, 3H), 1.65 (m, 8H). IR (KBr, cm⁻¹) 1690(C═O).

MS, m/z 460 (M⁺).

Analysis for: C₂₂ H₂₆ N₃ O₃ Br.HCl: Calculated: C, 53.19; H, 5.48; N,8.46. Found: C, 52.84; H, 5.64; N, 8.33.

EXAMPLE 285-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(5-bromo-3-pyridinylcarbonyl)-3-pyrazolidinone

Following the general procedure of Example 25, the reaction of5-bromonicotinyl chloride (from 2 g of 5-bromonicotinic acid, which istreated with oxalyl chloride/dimethylformamide in benzene, 9.9 mmol, 1.4equiv) in tetrahydrofuran gives, after recrystallization from hexanesand methylene chloride, 0.7 g (21%) of a white solid identified as5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(5-bromo-3-pyridinylcarbonyl)-3-pyrazolidinone:mp 139°-141° C. ¹ H NMR (d⁶ -DMSO, 400 MHz) δ8.83 (d, J=2 Hz, 1H), 8.65(d, J=2 Hz, 1H), 8.17 (t, J=2 Hz, 1H), 7.00 (s, 1H), 6.93 (s, 2H), 4.76(m, 1H), 4.42 (t, J=7 Hz, 1H), 3.72 (s, 3H), 3.39 (dd, J=8, 17 Hz, 1H),2.85 (dd, J=6, 17 Hz, 1H), 2.72 (s, 3H), 1.92-1.48 (m, 8H). IR (KBr,cm⁻¹) 3420, 2940, 1755, 1660, 1600, 1510, 1430, 1440, 1320, 1255, 1230,1150.

MS m/e (relative intensity) 475/473 (8/7, M⁺), 407/405 (7/5), 289 (30),221 (100), 186/184 (17/21), 150 (49).

Analysis for: C₂₂ H₂₄ BrN₃ O₄ : Calculated: C, 55.71; H, 5.10; N, 8.86.Found: C, 55.34; H, 5.05; N, 8.80.

EXAMPLE 295-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-[3-(3-pyridinyl)propyl]-3-pyrazolidinonequarter dichloromethane

To a solution of5-[3-(cyclopentyloxy)-4-methoxy-phenyl]-1-methyl-3-pyrazolidinone (1.10gms, 3.79 mmol), NaH (0.15 gms, 60%, 3.75 mmol), and dimethylformamide(15 mls) is added a solution of 1-bromo-3-(3-pyridinyl)propane [seeMioque, M., and Gautier, J. A. (1961). C. R. Hebd. Seances Acad. Sci.252, 2416.] (1.66 gms, 8.30 mmol) in dimethylformamide (5 mls). Thereaction is immersed in an oil bath (65° C.). After 20 hoursdimethylformamide is removed in vacuo, the residue is diluted inmethylene chloride, washed with saturated aqueous NaHCO₃ and dried overNa₂ SO₄. The product was concentrated and chromatographed (SiO₂ :1) 1:1ethyl acetate:hexane; 2) 2:1 ethyl acetate:hexane; 3) ethyl acetate; 4)3% methanol:ethyl acetate) to yield 0.85 gms (52%) of an oil. ¹ H NMR(DMSO-d₆, 400 MHz) δ8.40 (m, 2H), 7.55 (m, 1H), 7.25 (m, 1H), 6.95 (s,1H), 6.85 (m, 1H), 5.75 (s, 0.5H) 4.70 (m, 1H), 4.00 (m, 1H), 3.70 (s,3H), 3.60 (m, 1H), 3.10 (m, 1H), 2.55 (s, 3H), 2.45 (m, 4H), 1.75 (m,4H), 1.65 (m, 4H), 1.50 (m, 2H). IR(KBr, cm⁻¹) 1685 (C═O).

MS, m/z 410 (M⁺).

Analysis for: C₂₄ H₃₁ N₃ O₃.0.25CH₂ Cl₂ : Calculated: C, 67.62; H, 7.37;N, 9.75. Found: C, 67.50; H, 7.24; N, 9.55.

EXAMPLE 302-[(E)-3-(5-bromo-3-pyridinyl)-2-propenyl]-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinonehemi(dichloromethane) A. 3-(5-bromo-3-pyridinyl)prop-2-en-1-ol

A solution of diisobutylaluminum hydride (DIBAL-H, 8.02 mls, 1.54M intoluene) in ether (50 mls) is cooled to -78° C. under N₂. A solution of3-(5-bromo-3-pyridinyl)-2-propenoic acid ethyl ester [see Nishikawa, Y.,et al.(1989) J. Med. Chem. 32, 583-593] (1.54 gms, 6.00 mmol) in ether(50 mls) is added. After one hour the dry ice/acetone bath is removedand the mixture is diluted with methylene chloride, dried over Na₂ SO₄,evaporated and chromatographed (1:1 ethyl acetate:hexane followed by 2:1ethyl acetate:hexane) to yield 1.08 gms of an oil (84%). ¹ H NMR (DMSO,300 MHz) δ8.60 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 6.60 (m, 2H), 5.00(s, 1), and 4.10 (d, J=3.8 Hz, 2H).

B. 3-(5-bromo- 3-pyridinyl)-1-chloroprop-2-ene

A solution of 3-(5-bromo-3-pyridinyl)prop-2-en-1-ol (0.85 gms, 3.97mmol) is diluted with methylene chloride (20 mls). Thionyl chloride(0.27 mls, 97%, leq) is added at room temperature. After one hour asecond equivalent of thionyl chloride is added. The reaction isneutralized with saturated aqueous NaHCO₃ after an additional hour andextracted with methylene chloride. The organic layer is dried over Na₂SO₄ and evaporated to yield 0.70 gms of an oil (76%). ¹ H NMR (CDCl3,300 MHz) δ8.90 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 6.70 (m, 2H), and4.30 (d, J=3.8 Hz, 2H).

C.2-[(E)-3-(5-bromo-3-pyridinyl)-2-propenyl]-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinonehemi(dichloromethane)

To a stirred solution of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (1.12gms, 3.86 mmol) in dimethylformamide (10 mls) and NaH (0.16 gms, 60%,4.0 mmol) is added 3-(5-bromo-3-pyridinyl)-1-chloroprop-2-ene (0.85 gms,3.66 mmol). Dimethylformamide is removed in vacuo. The residue isdiluted with methylene chloride, washed with saturated aqueous NaHCO₃,dried over Na₂ SO₄, concentrated, and chromatographed (SiO₂ :1) hexane;2) 1:1 ethyl acetate:hexane; 3) 2:1 ethyl acetate:hexane; 4) 4:1 ethylacetate:hexane; 5) ethyl acetate; 6) 9:1 ethyl acetate:methanol) toyield 0.50 gms(28%) of an oil. ¹ H NMR (DMSO, 400 MHz) δ8.55 ppm (m,2H), 8.10 (m, 1H), 6.95 (s, 1H), 6.85 (s, 1H), 6.55 (d, J=16.2 Hz, 1H),6.45 (d of t, J=17.1 Hz, J'=5.5 Hz, 1H), 5.75 (s, 1H), 4.65 (m, 1H),4.35 (m, 1H), 4.05 (m,1H), 3.95 (m,1H), 3.70 (s,3H), 3.10 (m,1H), 2.55(s,3H), 2.45 (m,1H), 1.60 (m,6H), 1.45 (m,2H). IR(CHCl₃, cm⁻¹) 1690(C═O).

MS, m/z 486 (M⁺).

Analysis for: C₂₄ H₂₈ N₃ O₃.0.5 CH₂ Cl₂ : Calculated: C, 55.64; H, 5.52;N, 7.94. Found: C, 55.82; H, 5.78; N 7.94.

EXAMPLE 312-acetyl-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinonehydrochloride

5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (0.500g) is dissolved in acetic anhydride (15 mL). The resulting solution iswarmed to reflux for 2 hours, cooled to room temperature andconcentrated in vacuo to afford an oil. This residue is dissolved inether and treated with ethanolic HCl at room temperature. The resultingsolid is stirred for 4 hours at room temperature, collected by suctionand dried in vacuo to afford the title compound as a white powder (0.621g; 98%) mp: 82°-85° C. ¹ H NMR (DMSO-d₆, 400 MHz) δ6.88 (m, 3H); 3.85(s, 3H); 2.82 (s, 3H); 2.52 (s, 3H); 2.00 (m, 2H); 1.84 (m, 3H); 1.64(m, 2H). IR (KBr, cm⁻¹) 1730.

MS (EI, m/e) 332 (M+).

Analysis for: C₁₈ H₂₄ N₂ O₄.HCl: Calculated: C, 58.61; H, 6.83; N, 7.59.Found: C, 58.41; H, 6.85; N, 7.80.

EXAMPLE 325-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(3-pyridinylcarbonyl)-3-pyrazolidinonehemihydrate

To a solution of nicotinic acid (0.60 gms, 4.87 mmol) in benzene (5 mls)and dimethylformamide (0.05 mls, 0.646 mmol) is added oxalyl chloride(0.46 mls, 5.27 mmol) at room temperature. After 20 hours, the crudemixture is evaporated to 0.7 gms material. The crude product is added toa solution of5-[3-(cyclopentyloxy)-4-methoxy-phenyl]-1-methyl-3-pyrazolidinone (0.70gms, 2.41 mmol), NaH (0.1 gms, 60%, 2.5 mmol), and dimethylformamide (5mls). The reaction is immersed in an oil bath (65° C.) and stirred 20hours. Dimethylformamide is removed in vacuo. The residue is dilutedwith methylene chloride, washed with saturated aqueous NaHCO₃ and driedover Na₂ SO₄. The product is concentrated, chromatographed (ethylacetate), and recrystallized from methylene chloride/hexane to yield 275mg of a white solid (28%, mp 83°-84° C.). ¹ H NMR (DMSO-d₆, 400 MHz)δ8.70 (m,2H), 7.90 (m,1H), 7.65 (m,1H), 7.05 (s,1H), 6.95 (s,1H), 4.75(m,1H), 4.40 (m,1H), 3.70 (s,3H), 3.45 (m,1H), 2.85 (m,1H), 2.75 (s,3H),1.85 (m,2H), 1.70 (m,4H), 1.55 (m,2H).

IR(KBr, cm⁻¹) 1760, 1665 (C═O). MS, m/z 395 (M⁺).

Analysis for: C₂₂ H₂₅ N₃ O₄.1/2 (H₂ O): Calculated: C, 65.33; H, 6.48;N, 10.39. Found: C, 65.18; H, 6.08; N 10.26.

EXAMPLE 332-[(E)-3-(5-bromo-3-pyridinyl)-1-oxo-2-propenyl]-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone

A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.20 mmol, 0.230 g), 1-hydroxybenzotriazole hydrate (1.20 mmol, 0.162g) and 3-(5-bromo-3-pyridyl)propenoic acid (1.20 mmol, 0.274 g [seeNishikawa, et al, J Med Chem, 32, 583 (1989)] is suspended in drymethylene chloride (20 mL) at room temperature and stirred for 2 hours.To the suspension is added a solution of5-[3(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (1.20mmol, 0.340 g) in dry methylene chloride (10 mL) and the resultingmixture is stirred at room temperature overnight followed by reflux for24 hours. The homogenous solution is cooled to room temperature and thevolatiles are removed in vacuo. The residue is partitioned between ethylacetate (50 mL) and 1N NaOH (50 mL), the aqueous phase extracted withethyl acetate (50 mL) and the combined organics are washed with water(50 mL) and dried (Na₂ SO₄). Concentration in vacuo affords a whitefoam, which is purified via flash chromatography (SiO₂ : concentrationgradient ranging from 5% ethyl acetate/methylene chloride to 15% ethylacetate/methylene chloride) to give the title compound as a white solidwhich is triturated with ether and hexane and dried in vacuo at 50° C.to provide analytically-pure material (0.52 mmol, 0.260 g, 52%). H-NMR(DMSO-d₆, 400 MHz) δ8.82 (d, 1H, J=1.7 Hz); 8.66 (d, 1H, J=1.7 Hz); 8.41(t, 1H); 7.71 (d, 2H, J=2.4 Hz,); 6.98 (d, 1H, J=1.5 Hz); 6.89 (m, 2H);4.70 (m, 1H); 4.47 (dd, 1H, J=0.6, 1.7 Hz); 3.70 (s, 3H); 3.65 (m, 1H);2.84 (s, 3H); 2.77 (m, 1H); 1.80 (m, 2H); 1.62 (m, 4H); 1.49 (m, 2H). IR(KBr, cm⁻¹) 3460, 2940, 2860, 1748, 1660, 1623, 1515, 1445, 1435, 1425,1326, 1260, 1235, 1208, 1150, 1130, 1015, 990, 962, 848, 680.

MS (EI, m/e (%)) 502 (100), 500 (94), 291 (36), 234 (28).

Analysis for: C₂₄ H₂₆ BrN₃ O₄ : Calculated: C, 57.61; H, 5.24; N, 8.40.Found: C, 57.39; H, 5.46; N, 8.31.

EXAMPLE 345-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-(phenylmethyl)-3-pyrazolidinone

Sodium hydride (0.41 g of a 60% dispersion in mineral oil, 10.3 mmol,1.1 equiv) is added to a solution of5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-pyrazolidinone (2.6 g, 9.4mmol, 1.0 equiv) in anhydrous N,N-dimethylformamide (20 mL), and thereaction mixture is stirred at room temperature for 20 minutes. Benzylbromide (1.1 mL, 9.3 mmol), 1.0 equiv) in N,N-dimethylformamide is addeddropwise and the resulting mixture is stirred at 70° C. for 60 hours.The solvent is removed in vacuo and the residue is taken up in methylenechloride, washed once with water, and then dried (Na₂ SO₄). Afterchromatography on silica gel with hexanes/ethyl acetate, 1.5 g of solidis triturated with hexanes and ethyl acetate to give 1.0 g (29%) of awhite solid identified as5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-(phenylmethyl)-3-pyrazolidinone:mp 108°-110° C. ¹ H NMR (d⁶ -DMSO, 400 MHz) δ9.50 (s, 1H), 7.37-7.21 (m,5H), 6.89-6.79 (m, 3H), 4.70 (m, 1H), 4.17 (dd, J=5, 8 Hz, 1H), 3.97 (ABquartet, J=13 Hz, 1H), 3.80 (AB quartet, J=13 Hz, 1H), 3.69 (s, 3H),2.99 (dd, J=8, 16 Hz, 1H), 2.17 (dd, J=5, 16 Hz, 1H), 1.91-1.49 (m, 8H).IR (KBr, cm⁻¹) 3420, 3150, 3020, 2960, 2860, 1690, 1590, 1515, 1450,1430, 1375, 1340, 1260, 1230.

MS, m/e (relative intensity) 366 (19, M⁺), 207 (28), 175 (41), 150 (57),135 (47), 91 (100).

Analysis for: C₂₂ H₂₆ N₂ O₃ : Calculated: C, 72.11; H, 7.15; N, 7.64.Found: C, 72.06; H, 6.96; N, 7.63.

EXAMPLE 355-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-ethyl-3-pyrazolidinone

Following the general procedure of Example 34, reaction with bromoethane(0.7 mL, 9.4 mmol, 1.0 equiv) gives, after chromatography on silica gelwith hexanes/ethyl acetate, 0.35 g of solid, which is recrystallizedfrom hexanes and ethyl acetate to yield 0.25 g (8.6%) of a white solididentified as5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-ethyl-3-pyrazolidinone: mp144°-148° C. ¹ H NMR (d⁶ -DMSO, 400 MHz) δ9.53 (s, 1H), 6.94 (m, 1H),6.87 (m, 2H), 4.75 (m, 1H), 4.03 (t, J=8 Hz, 1H), 3.70 (s, 3H), 2.87(dd, J=8, 16 Hz, 1H), 2.71 (dq, J=7, 12 Hz, 1H), 2.53 (dq, J=7, 12 Hz,1H), 2.21 (dd, J=8, 16 Hz, 1H), 1.92-1.48 (m, 8H), 0.98 (t, J=7 Hz, 3H).IR (KBr, cm⁻¹) 3420, 3160, 2960, 1680, 1590, 1515, 1445, 1430, 1380,1350, 1255, 1230.

MS, m/e (relative intensity) 304 (22, M⁺), 236 (8), 177 (100), 150 (78),135 (40).

Analysis for: C₁₇ H₂₄ N₂ O₃ : Calculated: C, 67.08; H, 7.95; N, 9.20.Found: C, 66.70; H, 7.59; N, 9.12.

EXAMPLE 36

The following assay is employed to assess the ability of the compound ofthe invention to inhibit PDE IV.

A solution containing PDE IV is prepared from canine tracheal muscle asfollows:

The dog is euthanized with an overdose of beuthanasia while underanesthesia induced by a 33 mg/kg IV bolus of Nembutal. The trachealismuscle is removed, cleaned of connective tissue, and minced thoroughly.Three to four grams of tissue is then homogenized in Tris-HCl buffer (pH7.8) using a Polytron. The homogenate is then centrifuged at 25,000×g(4° C.) for 30 minutes. The supernatant is decanted and filtered throughfour layers of gauze, and applied to a 40 cm×2 cm DEAE-Sepharose columnthat is equilibrated with Tris-HCl buffer (pH 7.8). The column is thenwashed with an additional 240 mL of buffer to remove unbound proteins.PDE is eluted using 450 mL of Tris-HCl buffer containing a lineargradient of 0.0-1.0M Na-acetate (80 mL/hr), and 7.5 mL fractions arecollected. Each fraction is assayed for cAMP- and cGMP- metabolizing PDEactivity. Fractions eluting at approximately 0.6M Na-acetate, andcontaining cAMP but not cGMP metabolic activity are pooled and used as aPDE stock solution for assaying PDE IV inhibitory activity.

PDE IV activity is assayed [as described in Thompson et al., Advances inCyclic Nucleotide Research, 10, 69 (1979)] at 30° C. in a reactionmixture containing: 10 mM Tris-HCl (pH 7.8), 5 mM MgCl₂, 1 mMβ-mercaptoethanol, 1 μM ³ H-cAMP, 10 μM CI-930, PDE IV stock solution,and the desired concentration of test compound. CI-930 is included as aninhibitor of the cyclic GMP-sensitive, cyclic AMP-selective PDE (PDEIII) that is also present in the PDE IV stock solution when prepared asdescribed above. The ability of a test compound to inhibit PDE IV isdetermined by measuring the reduction in cAMP metabolism produced by thetest compound and expressing it as a percentage of the reduction inducedby 10 μM rolipram, a potent inhibitor of PDE IV [see Beavo, Advances inSecond Messenger and Phosphoprotein Research, 22, 1 (1988)]. IC₅₀ 's arecalculated for each test compound as the concentration of test compoundthat inhibits PDE IV by 50%.

When tested in this assay, the compounds of the invention give thefollowing results.

                  TABLE 1                                                         ______________________________________                                        Compound of    IC.sub.50 of                                                   Example No.    PDE IV                                                         ______________________________________                                         1             3.4 × 10.sup.-7                                           2             6.8 × 10.sup.-7                                           3             8.2 × 10.sup.-7                                           4             4.4 × 10.sup.-7                                           5             39% (10.sup.-5)                                                 6             52% (10.sup.-5)                                                 7             39% (10.sup.-5)                                                 8             1.6 × 10.sup.-7                                           9             4.6 × 10.sup.-7                                          10             3.1 × 10.sup.-7                                          11             3.8 × 10.sup.-7                                          12             4.2 × 10.sup.-7                                              13A        1.2 × 10.sup.-8                                            13B          1.8 × 10.sup.-8                                          14             2.6 × 10.sup.-7                                          15             4.9 × 10.sup.-8                                          16             48% (10.sup.-5)                                                17             3.6 × 10.sup.-8                                          18             1.0 × 10.sup.-7                                          19             1.2 × 10.sup.-7                                          20             6.5 × 10.sup.-8                                          21             5.3 × 10.sup.-8                                          22             2.1 × 10.sup.-7                                          23             3.2 × 10.sup.-7                                          24             8.5 ×  10.sup.-8                                         25             1.5 × 10.sup.-6                                          26             1.7 × 10.sup.-7                                          27             9.4 × 10.sup.-7                                          28             3.5 × 10.sup.-7                                          29             1.6 × 10.sup.-7                                          30             5.0 × 10.sup.-8                                          31             9.8 × 10.sup.-7                                          32             3.4 × 10.sup.-7                                          33             8.1 × 10.sup.-8                                          34             5.8 × 10.sup.-8                                          35             4.1 × 10.sup.-6                                          ______________________________________                                    

The compounds tested in this assay exhibit significant activity ininhibiting PDE IV.

What is claimed is:
 1. A compound having the formula ##STR19## whereinR¹ is hydrogen or lower alkyl;R² is C₃₋₇ alkyl or C₃₋₇ cycloalkyl; R³ ishydrogen, lower alkyl, carboxyloweralkyl, lower alkoxycarbonyl, loweralkoxycarbonyl loweralkyl, C₆₋₁₀ aryl or C₁₂₋₁₆ aralkyl; R⁴ is ##STR20##B is a bond, NH or O; Y is O or S; A is a bond or --C═C--; n is 0-5; R⁵is ##STR21## R⁶ is hydrogen or halo; the dotted line represents anoptional double bond; or a pharmacologically acceptable salt thereof. 2.A compound as claimed in claim 1 wherein ##STR22## wherein R¹ is C₁₋₃alkyl;R² is C₄₋₆ alkyl or C₅₋₆ cycloalkyl; R³ is C₁₋₃ alkyl or C₁₂₋₁₆aralkyl; R⁴ is ##STR23## R⁵ is ##STR24## A is a bond or --C═C--; n is0-2; and R⁶ is hydrogen or halo.
 3. A compound as claimed in claim 1wherein ##STR25## wherein R¹ is lower alkyl;R² is n-butyl orcyclopentyl; R³ is methyl; R⁴ is ##STR26## R⁵ is ##STR27## R⁶ ishydrogen or halo.
 4. The compound of claim 1, having the name3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2,5-dihydro-2-methyl-5-oxo-N-(2-pyridinylmethyl)-1H-pyrazole-1-carboxamide.5. The compound of claim 1, having the name3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-N-(3-pyridinylmethyl)-1-pyrazolidinecarboxamide.
 6. The compound of claim 1, having the name5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(3-pyridinylmethyl)-3-pyrazolidinonehydrochloride dihydrate.
 7. The compound of claim 1, having the name2-[(5-bromo-3-pyridinyl)methyl]-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinonehydrochloride.
 8. The compound of claim 1, having the name5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(5-bromo-3-pyridinylcarbonyl)-3-pyrazolidinone.9. The compound of claim 1, having the name5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-[3-(3-pyridinyl)propyl]-3-pyrazolidinonequarter dichloromethane.
 10. The compound of claim 1, having the name2-[(E)-3-(5-bromo-3-pyridinyl)-2-propenyl]-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinonehemi(dichloromethane).
 11. The compound of claim 1, having the name5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-2-(3-pyridinylcarbonyl)-3-pyrazolidinonehemihydrate.
 12. The compound of claim 1, having the name2-[(E)-3-(5-bromo-3-pyridinyl)-1-oxo-2-propenyl]-5-[3-(cyclo-pentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone.